4-{8 4({60 hydroxybenzyl)piperidino{9 -4-fluorobutyrophenone derivatives as tranquilizers

ABSTRACT

Novel compounds which are neuroleptic agents useful as tranquilizers and having the formula WHEREIN R is hydrogen, halogen, such as chlorine, bromine or fluorine, alkyl having from 1 to 4 carbon atoms, alkoxy having from 1 to 4 carbon atoms, thioalkoxy having from 1 to 3 carbon atoms, trifluoromethyl, phenyl or phenoxy and may be attached to the phenyl ring in the ortho, meta or para position or pharmaceutically acceptable acid addition salts thereof. The novel compounds are produced by reacting (substituted) Alpha phenyl-4-piperidinemethanols or salts thereof with 4&#39;&#39;-fluoro-4halobutyrophenones.

United States Patent [191 Carr [ Dec. 3, 1974 FLUOROBUTYROPHENONEDERIVATIVES AS TRANQUILIZERS [75] Inventor: Albert A. Carr, Cincinnati,Ohio [73] Assignee: Richardson-Merrell Inc., New York,

22 Filed: May 3,1972

21 Appl. No 249,886

Related US. Application Data [63] Continuation of Ser. No. 93,495, Nov.27, 1970,

abandoned.

[52] US. Cl 424/267, 260/293.73, 260/293.8 [51] Int. Cl A61u 27/00 [58]Field of Search 424/267; 260/293.8, 293.73

[56] References Cited UNITED STATES PATENTS 4/1969 Janssen 260/293.8

OTHER PUBLICATIONS Chem. Abst., 70, 68126, (April 1969) Lunsford et al.

Primary Examiner-Stanley J. Friedman Attorney, Agent, or Firm-L. RuthHattan; Eugene O. Retter; George W. Rauchfuss, Jr.

[ S 7] ABSTRACT Novel compounds which are neuroleptic agents useful astranquilizers and having the formula HOH 7 Claims, N0 Drawings 4-4(a-HYDROXYBENZ YIJPI PERIDINO)-4- FLUOROBUTYROPHENONE DERIVATIVES ASTRANQUILIZERS RELATIONSHIP TO OTHER APPLICATIONS This application is acontinuation of application Ser. No. 93,495, filed Nov. 27, 1970 and nowabandoned.

FIELD OF INVENTION This invention relates to novel derivatives ofa-phenyl-4-piperidinemethanols and to processes for preparing the same.More particularly, it relates to novel derivatives of4-[4-(a-hydroxybenzybpiperidinol-4- fluorobutyrophenones which areneuroleptic agents useful as tranquilizers and to processes forpreparing the same.

SUMMARY OF THE INVENTION The novel derivatives of a-phenyl-4-piperidinemethanols of this invention may be represented by the formulawherein R is hydrogen, halogen, such as chlorine, bromine or fluorine,alkyl having from I to 4 carbon atoms, alkoxy having from I to 4 carbonatoms, thioalkoxy having from l to 3 carbon atoms, trifluoromethyl,phenyl or phenoxy and may be attached to the phenyl ring in the ortho,meta or para position or pharmaceutically acceptable acid addition saltsthereof. The novel compounds are produced by reacting (substituted)a-phenyl-4-piperidinemethanols or salts thereof with4'-fluoro-4-halobutyrophenones.

DETAILED DESCRIPTION OF INVENTION As examples of the substituents whichR may represent in the above formula, there may be mentioned, forexample, a hydrogen atom, methyl, iso-propyl, t-butyl, methoxy, ethoxy,CF phenyl. phenoxy, methylmercapto, or a halogen atom such as fluorine,chlorine, or bromine. The R substituent may be in the ortho, meta orpara position on the phenyl radical.

The preferred compounds of this invention are those of the above formulawherein R is fluorine, chlorine or Formula I a trifluoromethyl radicalsubstituted in the meta or-par'a position on the benzyl moiety. Thepreferred compounds are represented by the general formula Formula IIwherein R is fluorine, chlorine or trifluoromethyl and the R substituentis attached to the phenyl ring in the meta or para position.

The invention also includes the pharmaceutically acceptable acidaddition salts of the compound of the hereinbefore set forth formulae,optical isomers and salts thereof, such as those salts with inorganicacids, such as, for example, hydrochloric, hydrobromic, sulphuric,phosphoric acids and the like and with organic carboxylic acids such as,for example, acetic, propionic, glycolic, lactic, pyruvic, malonic,succinic, fumaric, malic, tartaric, citric, ascorbic, maleic,hydroxymaleic, and dihydroxymaleic, benzoic, phenylacetic,4-aminobenzoic, 4-hydroxybenzoic, anthranilic, cinnamic, salicylic,4-aminosalicylic, Z-phenoxybenzoic, 2-acetoxybenzoic, mandelic acid andthe like.

Illustrative of compounds of this invention are, for example,4'-fluoro-4-[4-(p-fluoro-a-hydroxybenzyl)- piperidino]-butyrophenone,4-[4-(p-chloro-ozhydroxybenzyl)piperidino14-fluorobutyrophenone,4-fluoro-4-[4-(m-trifluoromethyl-a-hydroxybenzyl)-piperidino]butyrophenone, 4'-fluoro-4-[4-(ahydroxybenzyl)piperidino]butyrophenone, 4-fluoro- 4-[4-(p-methyl-a-hydroxybenzyl)piperidino butyrophenone, 4-fluoro- -[4-( p-methoxy-a-hydroxybenzyl)piperidino]- butyrophenone, 4-[4-(p-t-butyl-a-hydroxybenzylpiperidino]-4'-fluorobutyrophenone, 4'-fluoro-4-[4-(p-phenoxy-a-hydroxybenzyl )piperidino]- butyrophenone, and4-fluoro-4-[4-(p-phenyl-ahydroxybenzyl )-piperidino]butyrophenone.

The novel compounds of this invention are neuroleptic agents useful astranquilizers in animals in the form of pharmaceutical preparationswhich contain the novel compounds suitable for oral or parenteraladministration. The pharmaceutical preparations can be in solid orliquid form such as, for example, tablets, capsules, solutions,suspensions or emulsions. The quantity of the novel compound, in theunitdosage with a significant amount of a pharmaceutically acceptablecarrier, can vary over a wide range, for example, to provide from about0.005 to l0 mg per kg of body weight of the animal per dose to achievethe desired tranquilizing effeet. The tranquilizing effect can beobtained, for example, by consumption of 0.525 milligram tablets taken Ito 4 times daily.

lllustratively, when the compound of Example l was orally administeredto mice at a dosage level of 0.35 mg/kg, the toxicity of d-amphetaminein grouped mice was inhibited in 50% of the mice when tested accordingto the procedures disclosed by J. Burn et al., Arch. Int. Pharmacodyn.ll3, 290-5 (1958), whereas a dosage level of 1.2 mg/kg of the knowntranquilizer chlorpromazine is required to inhibit the toxicity ofdamphetamine in 50% of similarly grouped mice. Similarly, when thecompound of Example 1 was orally administered to mice at a dosage levelof L2 mg/kg pernicious preening in mice was inhibited in 50% of the micewhen tested according to the test procedures disclosed by A. Kandel etal., Fed. Proc. I9 (1 Pt. I) 24 (1960).

The neuroleptic potency of the novel compounds of this invention is alsoillustrated by their effectiveness in blocking conditioned avoidancebehavior in rats and in producing catalepsy in mice. interference withthe forced motor performance on a rotating rod -is evi-' temperaturesabove and below this range. Generally,

the reaction is conducted over a period of from 1 to 3 days during whichtime any evolved water may be collected. As examples of suitablesolvents for this reaction there may be mentioned toluene, xylene,chlorobenzene, methyl isobutyl ketone, or lower alcohols such asethanol. propanol, butanol and the like.

After completion of the reaction, the reaction mixture is filtered andthe product isolated after removal of the solvent. Alternately, thefiltrate may be treated with mineral or organic acids and diethyl etherto give the corresponding salts of the product. The crude product isfiltered off, purified by recrystallization and dried. Suitable solventsfor recrystallization are methanol, ethanol, isopropyl alcohol,butanone, acetone, ethyl acetate, diethyl ether and the like.

The general method for the preparation of the compounds of thisinvention can be represented by the following reaction scheme:

(HIGH 1 if] (t) one 1- corresponding ketone derivative. This reductioncan be effected by several methods, preferably by catalytichydrogenation, or metal hydride reduction. Compound 1 may also beprepared by reacting a substituted phenyl Grignard reagent with4-pyridine carboxaldehyde or 4-cyanopyridine followed by catalyticreduction of the intermediates thus obtained. The oz-phenyl-4-piperidinemethanol derivative may be isolated as the free base or as asalt, for example, the hydrochloride, Representative substituteda-phenyllpiperidinemethanol starting materials which find use inpreparing the compounds of this invention are contained in Table l,hereinafter.

TABLE I R A? s llOll R M.P., C. l R M,P.. 259-261 p-OCH; 127-128.?)159.5-161 172.5- 142-1435 m-CF; 181.5483. 5

Hydrochloride salt.

The intermediate substituted phenyl 4-piperidyl ketones used inpreparing compound 1 may be prepared by a Friedel-Craft reaction ofbenzene or a substituted benzene with isonipecotic acid chloridehydrochloride or N-(trifluoroacetyl)-isonipecotic trifluoroaceticanhydride followed by aqueous potassium carbonate hydrolysis in thelatter case. Reaction of a substituted phenyl Grignard reagent with4-cyanopiperidine, which can be prepared by hydrolyzingN-trifluoroacetyl-4- cyanopiperidine with aqueous potassium carbonate,will also yield the intermediate ketones.

The 4-fluoro-4-halobutyrophenone, compound 2, is commercially availableor may be prepared by reacting w-halobutyryl halide with fluorobenzenein the presence of aluminum chloride. Also, compound 2 may be preparedby reacting p-fluorophenyl magnesium halide with w-halobutyronitriles.

Alternately the compounds of this invention may be prepared by treatingketalized derivatives of 4'-fluoro-4-[4-(substituted-a-hydroxybenzyl(piperidinolbutyrophenones witha dilute acid solution such as hydrochloric acid, sulfuric acid,p-toluenesulfonic acid, and the like, at room temperature for 3 to l2hours. The ketal intermediate may be prepared by the reaction of theappropriately ketalized 4 fluoro- 4-halobutyrophenone with theappropriate 4- benzoylpiperidine in a solvent such as toluene, butanol,isopropyl alcohol, and the like, with or without potassium iodide, and abase such as potassium carbonate, sodium carbonate, potassiumbicarbonate, or sodium bicarbonate, and subsequently reducing theproduct by catalytic hydrogenation or metal hydride reduction.

The butyrophenone alkylating agent may be ketalized using ethyleneglycol, 1,3-propanediol, 2-methyl-Z-ethyldioxolane, methanol and thelike in a suitable solvent containing a small amount of hydrochloricacid, sulfuric acid or p-toluenesulfonie ucitl.

llXAMlLliS The following examples are illustrative of the invention.

EXAMPLE 14'-fluoro-4-[4-(p-fluoro-a-hydroxybenzyl)piperidinolbutyrophenone Toa-(p-fluorophenyl)-4-piperidinemethanol obtained from 26.0 g (0.11 mole)of the corresponding hydrochloride salt in 100 ml of toluene were added40 g of potassium bicarbonate, 23.0 g (0.12 mole) of 4-chloro-4-fluorobutyrophenone and 0.1 g of potassium iodide. Theresulting mixture was stirred on a steam bath for 48 hours and theinorganic residue filtered off and washed with a small amount ofbutanone. The filtrate was diluted with anhydrous diethyl ether andtreated with etheral hydrogen chloride to give the hydrochloride salt of4'-fluoro-4-[4-(p-fluoro-ahydroxybenzyl)piperidino]butyrophenone. Thismaterial was recrystallized from methanolbutanone and then extracted asthe free base into chloroform after treatment with sodium hydroxidesolution. The chloroform extracts were dried over anhydrous magnesiumsulfate and concentrated to a residue which was recrystallized fromabsolute ethyl alcohol to give4'-fluoro-4-[4-(p-fluoroa-hydroxybenzyl)piperidino]butyrophenone,l48150C.

EXAMPLE 2 By the procedure described in Example 1 and using theappropriately substituted a-pheny1-4- piperidinemethanol, the followingcompounds were prepared:4-[4(p-chloro-a-hydroxybenzyl)piperidinol-4-fiuorobutyrophenone. M.P.148150C. 4-fluoro-4-[4-(m-trifluoromethyl-a-hydroxybenzyl-(piperidinol-butyrophenone. M.P. l28.5132.0C. (mandelic acid salt).

EXAMPLE 3 4-fluoro-4-[4-(a-hydroxybenzyl)pipeiidinol-butyr- Qah. 2r

To 75.7 g (0.4 mole) of a-phenyl-4- piperidinemethanol in 500 ml oftoluene was added 88.0 g (0.44 mole) of 4-chloro-4- fluorobutyrophenone,80.0 g of potassium bicarbonate and 0.1 g of potassium iodide. Thereaction mixture was stirred at 100C. for 46 hours, filtered and theresulting solution concentrated in vacuo to a solid residue, which wasrecrystallized from isopropyl alcohol to give the desired product. M.P.102C. (dec.)

EXAMPLE 4 By the procedure described in Example 3 and using theappropriately substituted a-phenyl-4- piperidinemethanol, the followingcompounds were prepared:

6 4"-fluoro-4-[ (p-methyl-a-hydroxybenzyl )piperidino1- butyrophenone.M.P. 144.5-145.5C. 4'-fluoro-4- 4-( p-methoxy-a-hydroxybenzylpiperidino]butyrophenone. M.P. 101102.5C. 4-[ 4-(p-t-hutyl-oz-hydroxybcnzyl )pipcridino 1-4- flUUfUhlliYTOphClN"1C. M.P.l I ll l2..5(. 4-lluoro-4-l 4-( p-pheuoxy-u-hytlroxybcnz'ylpiperidino[butyrophenone. M.P. l95.5l96.5C.

EXAMPLE 5 EXAMPLE 6 4-[4-( p-ethylmercapto-a-hydroxybenzyl )piperidino4'-fluorobutyrophenone To 25.1 g (0.1 mole) ofa-(p-ethylmercaptophenyl)- 4-piperidinemethano1 in 200 ml of toluene isadded 22.0 g (0.1 1 mole) of 4-chloro-4- fluorobutyrophenone, 20.0 g ofpotassium bicarbonate and 0.1 g of potassium iodide. The reactionmixture is stirred at C. for 32 hours, filtered and the resultingsolution concentrated in vacuo to a solid residue which may berecrystallized from ethanol to give the desired product.

EXAMPLE 7 Tablet Formulation As exemplary of a representative tabletformulation of an active compound of this invention, there may bementioned the following:

m (a) 4'-fluoro 4-l4-(p-fluoro-a-hydroxybenzyl)piperidinoIbutyrophenone25.0 mg. (b) Wheat starch 3.5 mg. (c) Lactose 10.0 mg. (d) Magnesiumstearate 0.5 mg.

A granulation obtained upon mixing lactose with the starch andgranulated starch paste is dried, screened and mixed with the activeingredient and magnesium stearate. The mixture is compressed intotablets weighing 39.0 mg. each.

1 claim:

1. A method of obtaining tranquilizing effects in a patient comprisingadministering to said patient from 0.005 to 10 milligrams per kilogramof body weight of the patient a compound of the formula l (lHOH lwherein R is a member selected from the group consist- "'ing ofchlorine, fluorine, bromine, alkyl having from 1 to 4 carbon atoms, oralkoxy having from 1 to 4 carbon atoms and is attached at the paraposition of the phenyl ring; or a pharmaceutically acceptable acidaddition salt thereof.

2. A method as claimed in claim 1 wherein said compound is4-fluoro-4-[4-(p-fluoro-a-hydroxybenzyl)- piperidino1butyrophenone or apharmaceutically acceptable acid addition salt thereof.

3. A method as claimed in claim 1 wherein said compound is4-[4-(p-chloro-a-hydroxybenzyl)piperidinol- 4-fluorobutyrophenone or apharmaceutically acceptable acid addition salt thereof.

4. A method as claimed in claim 1 wherein said compound is4-fluoro-4-[4-(p-methyl-a-hydroxybenzyl)- piperidinolbutyrophenone or apharmaceutically acceptable acid addition salt thereof.

5. A method as claimed in claim 1 wherein said com- JIIOll wherein R isa member selected from the group consisting of chlorine, fluorine,bromine, alkyl having from 1 to 4 carbon atoms, or alkoxy having from 1to 4 carbon atoms and is attached at the para position of the phenylring; or a pharmaceutically acceptable acid addition salt thereof, and asignificant amount of a pharmaceutically acceptable carrier.

1. A METHOD OF OBTAINING TRANSQUILIZING EFFECTS IN A PATIENT COMPRISINGADMINISTERING TO SAID PATIENT FROM 0.005 TO 10 MILLIGRAMS PER KILOGRAMOF BODY WEIGHT OF THE PATIENT A COMPOUND OF THE FORMULA
 2. A method asclaimed in claim 1 wherein said compound is 4''-fluoro-4-(4-(p-fluoro-Alpha -hydroxybenzyl)piperidino)butyrophenone or a pharmaceuticallyacceptable acid addition salt thereof.
 3. A method as claimed in claim 1wherein said compound is 4-(4-(p-chloro- Alpha-hydroxybenzyl)piperidino)-4''-fluorobutyrophenone or a pharmaceuticallyacceptable acid addition salt thereof.
 4. A method as claimed in claim 1wherein said compound is 4''-fluoro-4-(4-(p-methyl- Alpha-hydroxybenzyl)piperidino)butyrophenone or a pharmaceutically acceptableacid addition salt thereof.
 5. A method as claimed in claim 1 whereinsaid compound is 4''-fluoro-4-(4-(p-methoxy- Alpha-hydroxybenzyl)piperidino)butyrophenone or a pharmaceutically acceptableacid addition salt thereof.
 6. A method as claimed in claim 1 whereinsaid compound is administered in dosage units containing 0.5 to 25milligrams of said compound in tablets which are taken 1 to 4 timesdaily.
 7. A pharmaceutical composition comprising in unit dosage form,from about 0.5 to 25 milligrams of a compound of the formula